Multi-center evaluation of baseline neutrophil-to-lymphocyte (NLR) ratio as an independent predictor of mortality and clinical risk stratifier in idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess the potential of neutrophil-to-lymphocyte ratio (NLR) to predict outcomes in IPF. Methods: We adopted a two-stage discovery (n = 71) and validation (n = 134) design using patients from the UCL partners (UCLp) cohort. We then combined discovery and validation cohorts and included an additional 794 people with IPF, using real-life data from 5 other UK centers, to give a combined cohort of 999 patients. Data were collected from patients presenting over a 13-year period (2006-2019) with mean follow up of 3.7 years (censoring: 2018-2020). Findings: In the discovery analysis, we showed that high values of NLR (>/ = 2.9 vs < 2.9) were associated with increased risk of mortality in IPF (HR 2.04, 95% CI 1.09-3.81, n = 71, p = 0.025). This was confirmed in the validation (HR 1.91, 95% CI 1.15-3.18, n = 134, p = 0.0114) and combined cohorts (HR 1.65, n = 999, 95% CI 1.39-1.95; p < 0·0001). NLR correlated with GAP stage and GAP index (p < 0.0001). Stratifying patients by NLR category (low/high) showed significant differences in survival for GAP stage 2 (p < 0.0001), however not for GAP stage 1 or 3. In a multivariate analysis, a high NLR was an independent predictor of mortality/progression after adjustment for individual GAP components and steroid/anti-fibrotic use (p < 0·03). Furthermore, incorporation of baseline NLR in a modified GAP-stage/index, GAP-index/stage-plus, refined prognostic ability as measured by concordance (C)-index. Interpretation: We have identified NLR as a widely available test that significantly correlates with lung function, can predict outcomes in IPF and refines cohort staging with GAP. NLR may allow timely prioritisation of at-risk patients, even in the absence of lung function. Funding: Breathing Matters, GSK, CF Trust, BLF-Asthma, MRC, NIHR Alpha-1 Foundation.

A trial of intra-pleural bacterial immunotherapy in malignant pleural mesothelioma (TILT) - a randomised feasibility study using the trial within a cohort (TwiC) methodology.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive thoracic malignancy with a poor prognosis. Systemic immunotherapy is an effective frontline treatment for MPM, and there is a scientific rationale supporting the possible efficacy of local, i.e. intra-pleural immune modulators. Trial of intra-pleural bacterial immunotherapy (TILT) investigated the feasibility of performing a randomised trial of intra-pleural bacterial immunotherapy in people with MPM, using the trials within cohorts (TwiC) methodology. METHODS: TILT was a multicentre, three-armed, randomised, feasibility TwiC of intra-pleural OK432, BCG, or usual care in people with MPM. Eligible participants were identified from within the ASSESS-meso study, a prospective, longitudinal, observational cohort study, and were randomly selected to be offered a single dose of OK432 or BCG, via an indwelling pleural catheter. The primary outcome was feasibility, evaluated against prespecified recruitment, attrition and data completeness targets. The acceptability of trial processes and interventions was assessed during qualitative interviews with participants and family members at the end of the trial. TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004,727-23) and the ISRCTN Register on 04 December 2017. RESULTS: Seven participants were randomised from a planned sample size of 12; thus, the 66% recruitment rate target was not met. Two participants withdrew after randomisation, breaching the pre-stated attrition threshold of 10%. It was not possible to maintain blinding of control participants, which negated a fundamental tenet of the TwiC design. The trial processes and methodology were generally acceptable to participants and relatives, despite several recipients of intra-pleural bacterial agents experiencing significant local and systemic inflammatory responses. CONCLUSION: It was possible to design a clinical trial of an investigational medicinal product based on the TwiC design and to obtain the necessary regulatory approvals. However, whilst acceptable to participants and relatives, the TwiC design was not a feasible method of investigating intra-pleural bacterial immunotherapy in people with MPM. Future trials investigating this topic should consider the eligibility constraints and recruitment difficulties encountered. TRIAL REGISTRATION: TILT was registered prospectively on the European Clinical Trials Registry (EudraCT number 2016-004727-23 ) and the ISRCTN Register ( 10432197 ) on 04 December 2017.

Appropriate Medical Staffing Improves Patient Safety, Training and Doctor Wellbeing.

Background Cross-covering of medical and surgical specialities out-of-hours is a problem in many hospitals, leaving trainee doctors responsible out-of-hours for patients they have never met, in specialities where they do not normally work. This has implications for patient safety and doctor wellbeing. In our Trust, a historical decision resulted in trainee doctors in Trauma & Orthopaedics and Ear Nose and Throat Surgery being reallocated out-of-hours to cross-cover medical inpatients. This left one doctor cross-covering all surgical specialities, including General Surgery, Urology, Vascular, Ear, Nose and Throat surgery (ENT), Trauma & Orthopaedics (T&O) and Spinal Surgery. As the out-of-hours workload increased over time, this impacted negatively on patient safety and doctor wellbeing to a point where it became unsustainable. Methods Evidence of safety concerns relating to surgical night shifts was gathered from Exception Reporting data and anecdotally from the Postgraduate Doctor Forum. Once the scale of this problem was accepted by the hospital board, following the successful presentation of two Business Cases, 17 additional doctors were recruited. This recruitment reduced the cross-covering of specialities out-of-hours and enable adequate staffing throughout all departments. Qualitative evidence was gathered by surveying affected doctors before and after the change in order to assess its impact on doctor wellbeing, training and perceived patient safety. Quantitative analysis of Exception Reports and Immediate Safety Concerns was also performed. Results The survey results following the change were overwhelmingly positive, demonstrating a significant improvement in workload, rest breaks and quality of care for patients. Foundation doctors reported higher levels of confidence and enhanced training due to more consistent supervision. Job satisfaction improved, with 81% of surgical senior house officers reporting they would recommend their job, compared with 42% previously. Trends in out-of-hours Exception Reporting and patient safety concerns were analysed to show a moderate improvement following the intervention. Conclusion With the ever-increasing volume and complexity of patients presenting to global healthcare systems, it is key that staffing levels are safe and adequate in order to maintain patient safety and doctor wellbeing. This project has demonstrated how historic short-term fixes such as redeploying trainee doctors out of their home speciality and implementing cross-cover of multiple specialities can have detrimental long-term effects. Our preliminary data revealed multiple issues related to patient safety, junior doctor workload and lack of training opportunities. By using this data, and enlisting the help of multiple valued senior stakeholders, an acceptable Business Plan was approved by the Trust with a view to reversing these issues. The recruitment of additional Trust Grade doctors to create a third tier of the surgical out-of-hours cover has been instrumental in improving conditions within our Trust and has shown that adequate workforce planning is achievable when supported by robust evidence. This project could be used as a guide for other units seeking to make similar improvements.

Use of peripheral neutrophil to lymphocyte ratio and peripheral monocyte levels to predict survival in fibrotic hypersensitivity pneumonitis (fHP): a multicentre retrospective cohort study.

The factors determining disease course and survival in fibrotic hypersensitivity pneumonitis (fHP) have not been fully elucidated.The aim of this study was to describe the characteristics of patients with fHP in a real-world cohort and investigate factors associated with worse outcomes. We aimed to explore the use of neutrophil to lymphocyte ratio (NLR) and peripheral blood monocyte levels in predicting mortality. METHODS: A retrospective, multicentre, observational UK cohort study. RESULTS: Patients with fHP were significantly younger than those with idiopathic pulmonary fibrosis (IPF) (median age fHP 73 vs IPF 75 years) and were much more likely to be woman (fHP 61% vs IPF 26%). In almost half of all fHP cases (49%, n=104/211), no causative antigen was identified from either the history or specific antigen testing. Overall, fHP was associated with a better survival than IPF, although median survival of both groups was poor (fHP 62 months vs IPF 52 months).IPF survival in patients with a high NLR was significantly lower than those with a low NLR (44 vs 83 months). A monocyte count ≥0.95 K/uL also predicted significantly poorer outcomes for patients with IPF compared with <0.95 K/uL (33 vs 57 months). In contrast, NLR and monocyte count did not predict survival in the fHP cohort. CONCLUSIONS: Although fHP has a statistically lower mortality than IPF, absolute survival time of both conditions is poor. High baseline NLR and absolute monocyte counts predict worse survival in IPF but not in fHP, highlighting the potential for divergence in their pathogenic mechanisms.

Linear probe 19-gauge endobronchial ultrasound diagnosis of a benign chondroid hamartoma.

We report a case of a 68-year-old gentleman, found to have a right hilar soft tissue mass whilst undergoing CT staging for prostate cancer. MRI imaging showed a heterogenous, enhancing solid mass without evidence of fat content. A linear probe endobronchial ultrasound-guided transbronchial needle aspiration was performed using a 19G needle. This confirmed the diagnosis of a benign chondroid hamartoma, avoiding the need for more invasive surgical biopsy.

Lesson of the month 2: Dry skin, yellow nails and breathlessness.

Interstitial lung disease (ILD) is a common clinical problem, representing a group of diseases consisting of inflammation and progressive fibrosis of the lung. In some cases, an underlying cause is not identified; however, a significant proportion of ILD is associated with connective tissue disease (CTD). A detailed history and examination is the most important part of the assessment of patients with suspected ILD and will direct further investigation. This case illustrates the importance of identifying the symptoms and signs of CTD when assessing a patient with ILD. In addition, we describe an unusual presenting manifestation of yellow nails, which is not a recognised feature of CTD-ILD, but improved following immunomodulatory treatment for the overall condition.

Endobronchial and transbronchial biopsy experience: A United Kingdom survey.

BACKGROUND: Trainees are performing fewer bronchoscopies as a result of the increased use of endobronchial ultrasound-guided transbronchial needle aspiration. Workforce planning and changes in trainee working patterns may also have compounded this situation. We investigated current trends in endobronchial biopsy (EBB) and transbronchial biopsy (TBB) training and competency in respiratory trainees and consultants across the United Kingdom. METHODS: We performed a national survey and received 131 online responses from 58 consultants and 73 registrars across 13 United Kingdom deaneries. RESULTS: A significant proportion (31%) of consultants, more than half of which were new consultants, had performed <500 bronchoscopies. Bronchoscopic biopsy experience varies widely across trainees and consultants (9.1% of senior trainees and 14.3% of new consultants had performed <100 bronchoscopies). Most trainees and some new consultants reported performing relatively low numbers of EBB (13% <20 and 52% <50 procedures) and TBB (75% of trainees, 36% of new consultants, 12% of established consultants <10 procedures). Significant numbers of trainees do not feel competent in EBB (24%) and TBB (89% of junior trainees, 64% of senior trainees) and some consultants (24% of new and established consultants) wish for support with TBB. CONCLUSIONS: These results have implications for future specialist training, curriculum planning, and service configuration. Training and performance of EBB and TBB may become concentrated in centers with an adequate volume of these procedures. Higher volumes of EBB and TBB may well be more likely to occur paradoxically in centers without endobronchial ultrasound-guided transbronchial needle aspiration; however, this hypothesis requires further study.

Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection: A Retrospective Case Review From Six UK Centers.

OBJECTIVE: Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014. METHODS: Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. RESULTS: Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P = .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs < 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P = .6). CONCLUSIONS: This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.

The effects of Provent on moderate to severe obstructive sleep apnoea during continuous positive airway pressure therapy withdrawal: a randomised controlled trial.

OBJECTIVES: The aim of this study was to test the effectiveness of Provent, an expiratory nasal resistance valve, to prevent the recurrence of OSA following CPAP withdrawal. DESIGN: Randomised, partially blinded, parallel, placebo-controlled trial. SETTING: Outpatient sleep clinics in the UK (Oxford) and Switzerland (Zurich). PARTICIPANTS: 67 patients with OSA receiving CPAP were randomised to one of three groups for 2 weeks: continuing CPAP, Provent or placebo Provent. MAIN OUTCOME MEASURES: Primary outcomes included for Provent versus placebo Provent, OSA severity (oxygen desaturation index (ODI), apnoea-hypopnoea index (AHI)) and Epworth Sleepiness Scale (ESS) score. Secondary outcomes for Provent versus placebo Provent included ODI from ambulatory pulse oximetry and blood pressure (BP). For CPAP versus Provent, or CPAP versus placebo Provent, secondary outcomes included ODI/AHI, ESS and BP. RESULTS: 63 patients were included in the per protocol analysis. OSA recurred in the Provent (ODI 35.8, SD 17.4) and placebo Provent (ODI 28.2, SD 18.3) groups, and there was no significant difference in ODI, AHI and ESS between Provent and placebo Provent at 2 weeks (mean difference ODI -1.0, 95% CI -10.0 to +12.0, p=0.85; AHI +3.2, 95% CI -7.7 to +14.1, p=0.52; and ESS -1.4, 95% CI -4.1 to +1.4, p=0.33). ODI from ambulatory pulse-oximetry and BP at 2 weeks were not different in the Provent versus placebo Provent groups. ODI, AHI and BP, but not ESS, were significantly higher in the Provent and placebo Provent groups compared with CPAP. CONCLUSIONS: Provent cannot be recommended as an alternative short-term therapy for patients with moderate to severe OSA already on CPAP. TRIALREGNO: NCT01332175.